Diabetes mellitus (DM) is a disease characterized by sugar and lipid metabolic disorder, and there is a risk that it may lead to various pathognomonic complexities resulting from an abnormally high blood sugar level (blood glucose level). The number of patients with diabetes mellitus in the world is estimated to exceed 180 million as of 2006.
The onset of diabetes mellitus has been reported to relate to environmental factors such as overeating, obesity, lack of exercise in addition to genetic factors. Diabetes mellitus is mainly classified into type 1 diabetes mellitus (insulin-dependent diabetes mellitus (IDDM)) and type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus (NIDDM)). Most of the patients (about 90%) suffer from type 2 diabetes mellitus.
Type 1 diabetes mellitus is characterized by loss of insulin-secreting β cells of the islets of Langerhans in the pancreas and type 2 diabetes mellitus is caused by two factors which are deficient insulin secretion due to reduced glucose sensitivity of pancreatic β cells and reduced insulin sensitivity of peripheral tissues such as muscle, adipose and liver.
Currently, exercise therapy and diet therapy are used in the treatment and prevention of diabetes mellitus, and medication therapy is used as well.
A typical medication therapy in current use includes insulin therapy and oral hypoglycemic agents. The oral hypoglycemic agents (OHAs) include sulfonylureas (SUs), biguanides, α-glucosidase inhibitors (α GIs) and thiazolidine derivatives (TZDs).
However, these medicines have side effects such as hypoglycemia, liver damage and gastrointestinal disease, and therefore an effective method for using these medicines has been studied and developed. In addition, the research on a novel mechanism-based treatment and prevention method has been underway actively.
Recent studies of G protein-coupled receptors (GPCRs) have led to the discovery of GPR40 (G protein-coupled receptor 40), also known as free fatty acid receptor 1 (FFR1), which is a protein having seven transmembrane domains and whose ligand is a free fatty acid, in particular a mid- and long-chain fatty acid. GPR40 is known to highly express in the pancreas of rodents, in particular in pancreatic β cells. Meanwhile, GPR40 is shown to express in the brain as well as pancreatic β cells of human.
With regard to the function of GPR40, it is known that a free fatty acid, a ligand for GPR40, acts on GPR40 in pancreatic βcells, and thereby β cells secrete insulin depending on glucose level. In addition, analysis of GPR40 knockout mice reveals that GPR40 may be involved in pathology of obesity and diabetes mellitus.
As a GPR40-related disease, diabetes mellitus, hyperglycemia, impaired glucose tolerance, insulin resistance, impaired fasting glucose, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, ketoacidosis, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipemia, hyperlipoproteinemia, metabolic syndrome, obesity, atherosclerosis, etc. are known. For these reasons, attention has been drawn to GPR40 as a novel target of diabetes mellitus.